Peptide mimics of the cytokine receptor common gamma chain and methods and compositions for making and using the same

ABSTRACT

Peptides which mimic a loop on the γ-chain that either interact with a cytokine or a γ-chain partner receptor chain of a heterodimeric cytokine receptor are disclosed. The peptides consist of 5-25 amino acids and inhibit signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a γ-chain. Pharmaceutical compositions that comprise the peptides are disclosed. Methods of inhibiting signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a γ-chain, methods of inhibiting cytokine mediated cell growth, proliferation, function or activity, methods of treating patients suffering from a disease disorder or condition characterized by cytokine mediated cell growth, proliferation, function or activity and methods of preventing a condition characterized by cytokine mediated cell growth, proliferation, function or activity are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Provisional Application No.60/036,941 filed Feb. 7, 1997, which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] The present invention relates to molecules which have structuresand functions that mimic the gamma chain that is shared by severalcytokine recpetors. The present invention relates to the use of suchmolecules to modulate cytokine activity and cytokine mediated functions.

BACKGROUND OF THE INVENTION

[0003] A family of related cytokine receptors including the receptorsfor IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 have been reported to sharea common protein chain, the γ-chain, for maximal ligand induced receptorbinding and signaling. The γ-chain is a member of the cytokine receptorsuperfamily which includes receptors for growth hormone, erythropoietin,IL-3, IL-2, IL-4, IL-7, IL-6 and GM-CSF. The γ-chain is a 64 kd proteinwith a fibronectin type II and CKR-SF domain which share structuralhomology.

[0004] The crystal structure of the human growth hormone receptor hasbeen published by deVos A. M., et al. 1992 Science 255:306-312, which isincorporated herein by reference, and shows that the receptors form ahomodimer to bind ligand and induce a signal. The receptors for IL-4have been shown to be in the form of a heterodimer consisting of IL-4αand the common γ-chain. A model for the human IL-4:IL-4-Receptorinteraction has been published by Gustchina, A. et al. 1995 PROTEINS:Structure, Function and Genetics 21:140-148, which is incorporatedherein by reference.

[0005] Cytokine:receptor complexes are very important mediators of manyimmune responses. For example, T cell growth and differentiation isregulated in part by IL-2, IL-4, IL-7, IL-9, and IL-15. These cytokineshave also been reported to play a role in other immunological functionsas well.

[0006] Without the γ-chain, the cytokine receptors which normally formcomplexes with the γ-chain are much less efficient in binding theirligands and thus transmitting their signals to the target cells.Evidence for the central role of the γ-chain includes the findings thatmutations in this receptor have been demonstrated to be the causativefactor in the development of severe combined immunodeficiency. Recently,Boussiotis, V. A. et al. 1994 Science 266:1039-1047, which isincorporated herein by reference, demonstrated that the development of Tcell anergy can be abrogated by signaling through this receptor byvarious means.

[0007] The function and activity of cells of the immune system areregulated and directed by cytokine:receptor interactions as is signalingwhich induces growth and proliferation. The activation of T cells and Bcells is regulated by cytokine:receptor interactions includingcytokine:receptor interactions involving receptors which include theγ-chain in a heterodimer.

[0008] There is a need for pharmaceutical compositions which caneffectively inhibit the immune responses mediated by cytokine:receptorinteractions. There is a need for a method of inhibiting cytokinemediated cell activation, function, growth and/or proliferation. Thereis a need for pharmaceutical compositions which can effectively inhibitsignaling that involves receptors which include the γ-chain. There is aneed for compositions and methods which can inhibit or suppress immuneresponses in order to therapeutically or prophylactically treatindividuals who have conditions, diseases or disorders involving immuneabnormal or undesirable immunological activity.

SUMMARY OF THE INVENTION

[0009] The present invention relates to peptide mimics of the loops onthe γ-chain which either interact with cytokines or the partners of theγ-chain in heterodimeric cytokine receptors that include the γ-chain.The peptides of the present invention are based on human and murineγ-chain sequences. The sequences homology for the human and murineγ-chain is high (71% identical and 82% similar) making the translationfrom one species to the next more direct.

[0010] The peptide mimics bind to the cytokine or partner receptor andinhibit cytokine activity. Inhibitors of the common γ-chain inhibit thefunction of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 by preventing theirbinding to their respective receptors. Thus, the inhibition of thesecytokine mediated events leads to immuno-suppressive responses which arebeneficial for the prevention or treatment of numerous auto-immunediseases and graft rejection following various types of transplantprocedures as well as diseases associated with hyperproliferation of Tcells and/or B cells. For example, many lymphomas are dependent on someof these cytokines (IL-2 for T cell lymphomas and IL-4 for B celllymphomas) for growth.

[0011] The present invention relates to peptides that consist of 5 to 25amino acids including: SEQ ID NO:1 IQLYQTF, SEQ ID NO:2 IHLYQTF, SEQ IDNO:3 CLQYLV, SEQ ID NO:4 CLEHLV, SEQ ID NO:5 CLQYLT, SEQ ID NO:6 CLEHLT,SEQ ID NO:7 CLQYLTQ, SEQ ID NO:8 CLEHLTQ, SEQ ID NO:9 PIAGSSQQ, SEQ IDNO:36 PICGSSQQ, SEQ ID NO:10 PLCGSAQH, SEQ ID NO:11 PLAGSAQH, SEQ IDNO:12 NHEPRFLS, SEQ ID NO:13 DYRHKFSL, SEQ ID NO:14 LNLQNL, SEQ ID NO:15LKLQNL, SEQ ID NO:16 NLSESQL, SEQ ID NO:17 KLSEQL or such an amino acidsequence with one or more conservative substitutions, wherein thepeptide inhibits cytokine mediated signal transduction.

[0012] The peptides of the invention preferably have constrainedconformations and most preferably are cyclic. In preferred embodiments,cysteine residues are provided at the termini of the peptides to formdi-sulfide bonds which result in the formation of cyclic peptides.

[0013] According to some embodiments of the present invention, peptidesare selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC, SEQID NO:19 CIHLYQTFC, SEQ ID NO:20 CLQYLVC, SEQ ID NO:21 CLEHLVC, SEQ IDNO:22 CLQYLTC, SEQ ID NO:23 CLEHLTC, SEQ ID NO:24 CLQYLTQC, SEQ ID NO:25CLEHLTQC, SEQ ID NO:26 CPIAGSSQQC, SEQ ID NO:37 CPICGSSQQC, SEQ ID NO:27CPLCGSAQHC, SEQ ID NO:28 CPLAGSAQHC, SEQ ID NO:29 CNHEPRFLSC, SEQ IDNO:30 CDYRHKFSLC, SEQ ID NO:31 CLNLQNLC, SEQ ID NO:32 CLKLQNLC, SEQ IDNO:33 CNLSESQLC, SEQ ID NO:34 CKLSESQLC and derivative peptides thereof.The derivative peptides consist of amino acid sequences which containone or more conservative substitutions. Conservative substitutionsinclude the following:

[0014] I may be substituted with V, A or L;

[0015] Q may be substituted with N;

[0016] L may be substituted with V, A or I;

[0017] Y may be substituted with F;

[0018] V may be substituted with I, A or L;

[0019] S may be substituted with T;

[0020] A may be substituted with V, I or L;

[0021] N may be substituted with Q;

[0022] E may be substituted with D;

[0023] F may be substituted with Y;

[0024] D may be substituted with E; and

[0025] I may be substituted with V, A or L.

[0026] In some preferred embodiments, the V in sequences SEQ ID NO:3CLQYLV and SEQ ID NO:4 CLEHLV are substituted with T to improvesolubility in aqueous solutions. Accordingly, peptides SEQ ID NO:22CLQYLTC, SEQ ID NO:23 CLEHLTC, SEQ ID NO:24 CLQYLTQC and SEQ ID NO:25CLEHLTQC are provided.

[0027] The peptides of the invention are derived from sequences of themurine or human cytokine receptor common gamma chain.

[0028] The peptides correspond to murine cytokine receptor gamma commonchain residues SEQ ID NO:1 IQLYQTF (100-106), SEQ ID NO:3 CLQYLV(161-166), PICGSSQQ (207-214), SEQ ID NO:12 NHEPRFLS (181-188), SEQ IDNO:14 LNLQNL (124-129), SEQ ID NO:16 NLSESQL (142-148) and thecorresponding sequences from the human cytokine receptor gamma commonchain, i.e. SEQ ID NO: 2 IHLYQTF, SEQ ID NO:4 CLEHLV, SEQ ID NO:11PLAGSAQH, SEQ ID NO:13 DYRHKFSL, SEQ ID NO:15 LKLQNL and SEQ ID NO:17KLSEQL.

[0029] The peptides SEQ ID NO:18 CIQLYQTFC, SEQ ID NO:19 CIHLYQTFC, SEQID NO:20 CLQYLVC, SEQ ID NO:21 CLEHLVC, SEQ ID NO:26 CPIAGSSQQC, SEQ IDNO:37 CPICGSSQQC, SEQ ID NO:27 CPLCGSAQHC, SEQ ID NO:28 CPLAGSAQHC, SEQID NO:29 CNHEPRFLSC, SEQ ID NO:30 CDYRHKFSLC, SEQ ID NO:31 CLNLQNLC andSEQ ID NO:32 CLKLQNLC are modeled to mimic the regions of the cytokinereceptor gamma common chain predicted to interact with ligands and thepeptides SEQ ID NO:33 CNLSESQLC and SEQ ID NO:34 CKLSESQLC are modeledto mimic the regions of the cytokine receptor gamma common chainpredicted to interact with other cytokine receptor chains with which thegamma chain forms heterodimers as an active receptor complex.

[0030] According to the invention, the peptides of the invention inhibitcytokine mediated signaling that involves cytokine receptors whichinclude the gamma chain. Cytokines IL-2, IL-4, IL-7, IL-9, IL-13 andIL-15 each interact with receptor complexes that include the gammachain. Accordingly, the peptides of the invention can be used to inhibitIL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 signaling. Through thisinhibition, the peptides of the invention are useful to suppressimmunological responses and functions. For example, these cytokines areinvolved in immunological activity in which cells are induced to grow,proliferate and/or release factors, cytokines or other moleculesincluding antibodies. The peptides of the invention can be used toinhibit these activities.

[0031] Inhibition of T cell and/or B cell proliferation is useful in thetreatment of many diseases and conditions including, but not limited to,leukemia, lymphoma, graft versus host disease and other transplantrejections, allergies, asthma and autoimmune and inflammatory diseasessuch as rheumatoid arthritis, lupus, multiple sclerosis and myastheniagravis. The peptides of the invention can also inhibit the growth of Bcells and T cells and/or inhibit T cells and B cells from releasingsubstances. Thus, by inhibiting cell growth and/or proliferation and/orfunction of cells involved in the immune system, the peptides can beuseful to suppress the immune system.

[0032] The present invention relates to methods of preventing andtreating diseases involving or mediated by cells of the immune system.According to some embodiments of the invention, patients areadministered compounds of the invention in an amount sufficient tosuppress immune function sufficiently to have a therapeutic effect onpatients suffering from such diseases involving undesirable function,activity, growth or proliferation of cells of the immune system.According to some embodiments of the invention, patients areadministered compounds of the invention in an amount sufficient tosuppress immune function sufficiently to have a preventive effect onpatients at risk of developing diseases, disorders or conditionsinvolving undesirable function, activity, growth or proliferation ofcells of the immune system.

BRIEF DESCRIPTION OF THE FIGURES

[0033] FIGS. 1A-1D shows data from experiments described in Example 1testing peptides gamma-4 and gamma-5 of the invention as described inExample 1 to determine their effect on the response of cells toexogenous cytokine IL-2 or IL-4. The cell line used proliferates in theabsence of peptide. The data shows that the addition of peptide inhibitscell proliferation in response to addition of the IL-4 and that suchinhibition is dose dependent.

[0034]FIG. 2 shows data from experiments described in Example 1 testingpeptides of the invention as described in Example 1 to determine theireffect on the response of cells to exogenous murine IL-4. The cell lineused proliferates in the absence of peptide. The data shows that theaddition of peptide inhibits cell proliferation in response to additionof mIL-4 and that such inhibition is dose dependent.

[0035]FIG. 3 shows data from experiments described in Example 1 testingpeptides of the invention as described in Example 1 to determine theireffect on the response of cells to exogenous murine IL-2. The cell lineused proliferates in the absence of peptide.

[0036]FIG. 4 shows data from experiments described in Example 1 testingthe ability of peptides of the invention as described in Example 1 toinhibit mixed lymphocyte responses (MLR assays as described in Example2).

[0037]FIG. 5 shows data from experiments described in Example 1 testingthe ability of peptides of the invention as described in Example 1 toinhibit CH12.CX proliferation.

[0038] FIGS. 6A-6F shows data from experiments described in Example 2testing the ability of peptides of the invention as described in Example1 to inhibit cytokine mediated activity of various cell lines.

[0039]FIG. 7 shows data from experiments described in Example 2 testingthe ability of peptides of the invention as described in Example 1 toinhibit human IL-4 mediated activity.

[0040]FIG. 8 shows data from experiments described in Example 2 testingthe ability of peptides of the invention as described in Example 1 toinhibit cytokine mediated activity of cells in vivo.

DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention relates to molecules that have a molecularsurface similar to a molecular surface of cytokine receptor common gammachain. The peptides of the invention interact with molecules whichordinarily interact with the gamma chain and result in signaltransduction. Not wishing to bound by any theory, it appears that thepeptides of the invention thereby inhibit signal transduction byinhibiting cytokine:receptor binding either by binding to the cytokineor by binding to a cytokine receptor chain which forms heterodimers withthe gamma chain in order to form a functional receptor complex.

[0042] According to some embodiments of the present invention, theinvention can be represented by the formula:

R₁—R₂—R₃—R₄—R₅

[0043] wherein:

[0044] R₁, R₂, R₃, R₄ and R₅ taken together are 5-25 amino acids or lessand

[0045] R₁ is a linking moiety, preferably cysteine or penicillamine;

[0046] R₂ is 0-10 amino acids, preferably 0 amino acids;

[0047] R₃ is SEQ ID NO:1 IQLYQTF, SEQ ID NO: 2 IHLYQTF, SEQ ID NO:3CLQYLV, SEQ ID NO:4 CLEHLV, SEQ ID NO:5 CLQYLT, SEQ ID NO:6 CLEHLT, SEQID NO:7 CLQYLTQ, SEQ ID NO:8 CLEHLTQ, SEQ ID NO:9 PIAGSSQQ, SEQ ID NO:10PLCGSAQH, SEQ ID NO:11 PLAGSAQH, SEQ ID NO:12 NHEPRFLS, SEQ ID NO:13DYRHKFSL, SEQ ID NO:14 LNLQNL, SEQ ID NO:15 LKLQNL, SEQ ID NO:16NLSESQL, SEQ ID NO:17 KLSEQL or such an amino acid sequence with one ormore conservative substitutions;

[0048] R₄ is 0-10 amino acids, preferably 0 amino acids; and

[0049] R₅ is a linking moiety, preferably cysteine or penicillamine.

[0050] It is preferred that R₁ is cysteine or penicillamine. It is morepreferred that R₁ is cysteine.

[0051] It is preferred that R₂ is 0 amino acids.

[0052] It is preferred that R₃ is SEQ ID NO:1 IQLYQTF, SEQ ID NO: 2IHLYQTF, SEQ ID NO:3 CLQYLV, SEQ ID NO:4 CLEHLV, SEQ ID NO:5 CLQYLT, SEQID NO:6 CLEHLT, SEQ ID NO:7 CLQYLTQ, SEQ ID NO:8 CLEHLTQ, SEQ ID NO:9PIAGSSQQ, SEQ ID NO:10 PLCGSAQH, SEQ ID NO:11 PLAGSAQH, SEQ ID NO:12NHEPRFLS, SEQ ID NO:13 DYRHKFSL, SEQ ID NO:14 LNLQNL, SEQ ID NO:15LKLQNL, SEQ ID NO:16 NLSESQL or SEQ ID NO:17 KLSEQL.

[0053] It is preferred that conservative substititions include I, V, Aand L are interchangeable, Q and N are interchangeable, Y and F areinterchangeable, S and T are interchangeable and E and D areinterchangeable.

[0054] It is preferred that R₄ is 0-1 amino acids. It is preferred thatR₄ is 0 amino acids.

[0055] It is preferred that R₅ is cysteine or penicillamine. It is morepreferred that R₅ is cysteine.

[0056] In preferred embodiments, the compound is SEQ ID NO:18 CIQLYQTFC,SEQ ID NO:19 CIHLYQTFC, SEQ ID NO:20 CLQYLVC, SEQ ID NO:21 CLEHLVC, SEQID NO:22 CLQYLTC, SEQ ID NO:23 CLEHLTC, SEQ ID NO:24 CLQYLTQC, SEQ IDNO:25 CLEHLTQC, SEQ ID NO:26 CPIAGSSQQC, SEQ ID NO:27 CPLCGSAQHC, SEQ IDNO:28 CPLAGSAQHC, SEQ ID NO:29 CNHEPRFLSC, SEQ ID NO:30 CDYRHKFSLC, SEQID NO:31 CLNLQNLC, SEQ ID NO:32 CLKLQNLC, SEQ ID NO:33 CNLSESQLC or SEQID NO:34 CKLSESQLC.

[0057] The present invention provides synthetic peptides that are 5-25amino acids and comprise amino acid sequences from human or murinecytokine receptor gamma common chain. Non-gamma chain amino acidsequences are provided in some embodiments. The peptides areconformationally restricted, and are generally cyclized. In someembodiments, non-gamma chain sequences are included for the purposes ofconformational restriction. In embodiments that comprise both gammachain and non-gamma chain sequences, at least 20-25% of the amino acidsequence of the peptides of the present invention are derived from hegamma chain. It is preferred that greater than about 20-25% of the aminoacid sequence of the peptides of the present invention are derived fromthe gamma chain, more preferably 30-40% and more preferably greater than50%. In some embodiments, the percentage of amino acid sequence of thepeptides of the present invention derived from gamma chain is about 60%or about 75% or more.

[0058] The peptides of the present invention may be prepared by any ofthe following known techniques. Conveniently, the peptides may beprepared using the solid-phase synthetic technique initially describedin Merrifield (1963) J. Am. Chem. Soc. 15:2149-2154. Other peptidesynthesis techniques may be found, for example, in M. Bodanszky et al.,Peptide Synthesis, John Wiley & Sons, 2d Ed. (1976); Kent andClark-Lewis in Synthetic Peptides in Biology and Medicine, p. 295-358,eds. Alitalo, K., Partanen, P. and Vakeri, A., Elsevier SciencePublishers, (Amsterdam, 1985); as well as other reference works known tothose skilled in the art. A summary of peptide synthesis techniques maybe found in J. Stuart and J. D. Young, Solid Phase Peptide Synthelia,Pierce Chemical Company, Rockford, Ill. (1984). The synthesis ofpeptides by solution methods may also be used, as described in TheProteins, Vol. II, 3d Ed., p. 105-237, Neurath, H. et al., Eds.,Academic Press, New York, N.Y. (1976). Appropriate protective groups foruse in such syntheses will be found in the above texts, as well as in J.F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, NewYork, N.Y. (1973).

[0059] In general, these synthetic methods involve the sequentialaddition of one or more amino acid residues or suitable protected aminoacid residues to a growing peptide chain. Normally, either the amino orcarboxyl group of the first amino acid residue is protected by asuitable, selectively-removable protecting group. A different,selectively removable protecting group is utilized for amino acidscontaining a reactive side group, such as lysine.

[0060] Using a solid phase synthesis as an example, the protected orderivatized amino acid is attached to an inert solid support through itsunprotected carboxyl or amino group. The protecting group of the aminoor carboxyl group is then selectively removed and the next amino acid inthe sequence having the complementary (amino or carboxyl) group suitablyprotected is admixed and reacted with the residue already attached tothe solid support. The protecting group of the amino or carboxyl groupis then removed from this newly added amino acid residue, and the nextamino acid (suitably protected) is then added, and so forth. After allthe desired amino acids have been linked in the proper sequence, anyremaining terminal and side group protecting groups (and solid support)are removed sequentially or concurrently, to provide the final peptide.The peptide of the invention are preferably devoid of benzylated ormethylbenzylated amino acids. Such protecting group moieties may be usedin the course of synthesis, but they are removed before the peptides areused. Additional reactions may be necessary, as described elsewhere, toform intramolecular linkages to restrain conformation.

[0061] The present peptides may also be prepared by recombinant DNAtechniques, although such methods are not preferred because of the needfor purification and subsequent chemical modifications toconformationally restrain the peptides.

[0062] In addition to peptides which comprise L amino acids,pharmaceutical compositions according to the present invention maycomprise peptides made up of D amino acids. Because most enzymesinvolved in degradation recognize a tetrahedral alpha-carbon, theD-amino acids were utilized in order to avoid enzyme recognition andsubsequent cleavage. Our computer studies indicate that the same foldedpresentation of the peptide is accomplished by reversing the amino acidsequence, employing D-amino acids. Thus, peptides comprised of D aminoacids are less susceptible to degradation.

[0063] Conservative substitutions in the amino acid sequence may bemade. Those having ordinary skill in the art can readily designcompounds of the invention with conservative substitutions for CD8 aminoacids. For example, following what are referred to as Dayhof's rules foramino acid substitution (Dayhof, M. D. (1978) Nat. Biomed. Res. Found.,Washington, D.C. Vol. 5, supp. 3), amino acid residues in a peptidesequence may be substituted with comparable amino acid residues. Suchsubstitutions are well known and are based the upon charge andstructural characteristics of each amino acid.

[0064] Synthesized peptides may be circularized in order to mimic thegeometry of those portions as they occur in the gamma chain.Circularization may be facilitated by disulfide bridges between cysteineresidues. Alternatively, the peptides may be circularized by means ofcovalent bonds, such as amide bonds, between amino acid residues of thepeptide such as those at or near the amino and carboxy termini.

[0065] Peptides for use in pharmaceutical compositions of the presentinvention may be designed following the guidelines set out herein andusing well known processes. Methods of synthesizing peptides andcircularizing them may be performed routinely using standard techniquesand readily available starting materials.

[0066] The present invention relates to methods of therapeutically orprophylactically treating an individual suffering from or susceptible toa disease, condition or disorder associated with T cell or B cellgrowth, proliferation and/or secretion of biologically active material.The present invention relates to methods of therapeutically orprophylactically treating an individual suffering from or susceptible toa disease, condition or disorder by suppressing immunological responsesthrough the inhibition of cytokine mediated signal transduction.

[0067] Examples of diseases condition and disorders for which thepresent invention may be employed include T cell and B cell leukemiasand lymphomas, inflammatory and autoimmune diseases, allergies andconditions and rejections associated with transplantation protocols.

[0068] Those having ordinary skill in the art can readily identifyindividuals suspected of suffering from or being susceptible toconditions, diseases and disorders which can be effectively treated orprevented by inhibition of cytokine mediated immune responses effectedby the peptides of the invention. Those with ordinary skill in the artcould readily identify individuals for whom administration of thecompounds of the invention would be beneficial to alleviate or preventimmune responses. Treatment may be provided prophylactically or inresponse to symptoms associated with undesirable immune responses oractivity of cells of the immune system. Pharmaceutical compositionsuseful in the methods of the present invention comprise the compoundsdescribed herein.

[0069] The method of therapeutically or prophylactically treating anindividual comprises administering to such an individual an effectiveamount of a peptide according to the invention. A prophylacticallyeffective amount is an amount which is effective to prevent or decreasethe immune response associated with disease condition or disorder to beprevented. A therapeutically effective amount is an amount which iseffective to decrease or eliminate symptoms in an individual sufferingfrom such diseases, conditions and disorders, rejection. Those havingordinary skill in the art can readily and routinely determine the rangesof both prophylactically and therapeutically effective amounts of thepeptides of the invention without undue experimentation.

[0070] The present invention provides pharmaceutical compositions thatcomprise the peptides of the invention and pharmaceutically acceptablecarriers or diluents. The pharmaceutical composition of the presentinvention may be formulated by one having ordinary skill in the art.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield, which is incorporated herein by reference. In carrying outmethods of the present invention, conjugated compounds of the presentinvention can be used alone or in combination with other diagnostic,therapeutic or additional agents. Such additional agents includeexcipients such as coloring, stabilizing agents, osmotic agents andantibacterial agents.

[0071] For parenteral administration, the peptides of the invention canbe, for example, formulated as a solution, suspension, emulsion orlyophilized powder in association with a pharmaceutically acceptableparenteral vehicle. Examples of such vehicles are water, saline,Ringer's solution, dextrose solution, and 5% human serum albumin.Liposomes and nonaqueous vehicles such as fixed oils may also be used.The vehicle or lyophilized powder may contain additives that maintainisotonicity (e.g., sodium chloride, mannitol) and chemical stability(e.g., buffers and preservatives). The formulation is sterilized bycommonly used techniques. For example, a parenteral composition suitablefor administration by injection is prepared by dissolving 1.5% by weightof active ingredient in 0.9% sodium chloride solution.

[0072] The pharmaceutical compositions according to the presentinvention may be administered as a single dose or in multiple doses. Thepharmaceutical compositions of the present invention may be administeredeither as individual therapeutic agents or in combination with othertherapeutic agents. The treatments of the present invention may becombined with conventional therapies, which may be administeredsequentially or simultaneously. In some embodiments, compounds areadministered 1-2 days prior to transplantation, preferably 4-12 hours.Compounds may be delivered during transplantation procedures. In someembodiments, compounds are administered for 2 weeks to 2 months aftertransplantation procedures.

[0073] The pharmaceutical compositions of the present invention may beadministered by any means that enables the active agent to reach thetargeted cells. These methods include, but are not limited to, oral,topical, intradermal, subcutaneous, intravenous, intramuscular andintraparenteral modes of administration. The compounds may beadministered singly or in combination with other compounds. Thecompounds of the invention are preferably administered with apharmaceutically acceptable carrier selected on the basis of theselected route of administration and standard pharmaceutical practice.

[0074] The dosage administered varies depending upon factors such as:pharmacodynamic characteristics; its mode and route of administration;age, health, and weight of the recipient; nature and extent of symptoms;kind of concurrent treatment; and frequency of treatment. Usually, thedosage of peptide can be about 1 to 3000 milligrams per 50 kilograms ofbody weight; preferably 10 to 1000 milligrams per 50 kilograms of bodyweight; more preferably 25 to 800 milligrams per 50 kilograms of bodyweight. Ordinarily 8 to 800 milligrams are administered to an individualper day in divided doses 1 to 6 times a day or in sustained release formis effective to obtain desired results.

EXAMPLES Example 1

[0075] Novel peptide mimics that were derived from the sequence of thecytokine receptor common gamma chain were designed for the purpose ofinhibiting cytokine receptor signal transduction. Such peptides arecapable of inhibiting the functions of many immune cells which areresponsive to these cytokines and thus are useful in the treatment ofvarious maladies such as leukemia, lymphoma, inflammatory diseases,autoimmune disease, transplant rejection, allergies and others.

[0076] Based on the structural data, 5 sequences (γ1-5) were identifiedthat are predicted to interact with the ligands of the γ-chain and onesequence (γ6) that is predicted to interact with the heterodimericpartner receptors was synthesized. The sequences are as follows: MurineHuman % Identity γ1 (I₁₀₀->F₁₀₆) SEQ ID NO: 1 SEQ ID NO: 2 86 IQLYQTFIHLYQTF γ2 (C₁₆₁->V₁₆₆) SEQ ID NO: 3 SEQ ID NO: 4 67 CLQYLV CLEHLV γ3(P₂₀₇->Q₂₁₄) SEQ ID NO: 36 SEQ ID NO: 10 63 PICGSSQQ PLCGSAQH γ4(N₁₈₁->L₁₈₈) SEQ ID NO: 12 SEQ ID NO: 13 50 NHEPRFLS DYRHKFSL γ5(L₁₂₄->L₁₂₉) SEQ ID NO: 14 SEQ ID NO: 15 83 LNLQNL LKLQNL γ6(N₁₄₂->L₁₄₈) SEQ ID NO: 16 SEQ ID NO: 17 86 NLJSESQL KLSEQL

[0077] Peptides have been synthesized based on these sequences andcyclized by the addition of cysteine residues at either end anddisulfide bridging. We have tested the following murine peptides invitro for their ability to inhibit cytokine driven proliferation of celllines such as CTLL (T-cell) and CH12.CX (B-cell) as well as in MLRs:Peptide Sequence γ1 (I₁₀₀->F₁₀₆) SEQ ID NO: 18 CIQLYQTFC γ2 (C₁₆₁->V₁₆₆)SEQ ID NO: 20 CLQYLVC γ3 (P₂₀₇->Q₂₁₄) SEQ ID NO: 26 CPIAGSSQQC γ4(N₁₈₁->L₁₈₈) SEQ ID NO: 29 CNHEPRFLSC γ5 (L₁₂₄->L₁₂₉) SEQ ID NO: 31CLNLQNLC γ6 (N₁₄₂->L₁₄₈) SEQ ID NO: 33 CNLSESQLC γ2 lin. SEQ ID NO: 35ERCLQYLVQY γ2T (γ2 V->T) SEQ ID NO: 22 CLQYLTC

[0078] The murine sequences have been tested in at least two of theseproliferation assays. FIGS. 1A-1D, 2 and 3 show the ability of thesepeptides to inhibit IL-4 induced proliferation of CTLL's. FIG. 4 showsthe ability of these peptides to inhibit MLRs and FIG. 5 shows theability of these peptides to inhibit CH12.CX proliferation.

[0079] These data suggest that these peptides can in fact inhibitcytokine responses in vitro. These peptides do not appear to be toxic asthe CTLL proliferation to IL-2 is not affected.

Example 2

[0080] Experiments were performed to test the effect of each of peptidesgamma-1, gamma-2, gamma-3, gamma-4, gamma-5 and gamma-6 on differentcell types using several different assays. The data from the experimentsis shown in FIGS. 6A-6F. The assays were performed as follows:

[0081] CTLL Proliferation Assay: The murine IL-2- and IL-4-responsiveCTLL cell line was used to assess the ability of the gamma chainpeptides to inhibit the binding of these cytokines to their respectivereceptors. The cell line proliferates in responses to exogenously addedcytokine and inhibition of this proliferation by the peptides would be aresult of blocking the cytokines from interacting with their receptors.Briefly, 5000 CTLL cells are added to the wells of a 96 well microtitreplate. Either 10 U/ml r-mIL-2 or 1 ng/ml r-mIL-4 are added to thesewells along with titred amounts of the indicated peptides. Cultures areincubated at 37° C. for 24 hours and pulsed with ³H-TDR for the final 6hours to indicate amount of proliferation. Wells containing no peptideare deemed the positive response and well containing no peptide and nocytokine are deemed the background (bkg) proliferation. A percentresponse is calculated as follows: (CPM experimental−CPM bkg)/CPMpositive response-CPM bkg). All data are expressed in this manner.

[0082] CT4S Proliferation Assay: The murine IL-4 responsive CT4S cellline was used to assess the ability of the gamma chain peptides toinhibit the binding of IL-4 to its receptor. The cell line proliferatesin responses to exogenously added mIL-4 and inhibition of thisproliferation by the peptides would be a result of blocking the mIL-4from interacting with their receptors. Briefly, 5000 CT4S cells areadded to the wells of a 96 well microtitre plate. r-mIL-4 (50 pg/ml) isadded to these wells along with titred amounts of the indicatedpeptides. Cultures are incubated at 37° C. for 48 hours and pulsed with³H-TdR for the final 6 hours to indicate amount of proliferation. Wellscontaining no peptide are deemed the positive response and wellscontaining no peptide and no cytokine are deemed the background (bkg)proliferation. A percent response is calculated as follows: (CPMexperimental-31 CPM bkg)/(CPM positive response−CPM bkg). All data areexpressed in this manner.

[0083] CH12 Proliferation Assay: The CH12 murine B cell lymphoma, likemany lymphomas, is an IL-4 producing cell line that is also dependent onIL-4 for proliferation. No exogenous IL-4 is added to the wells of thesecultures. Briefly, 1500 cells are added to each well along with titredamounts of the indicated peptides. Cultures are incubated at 37° C. for48 hours and pulsed with ³H-TdR for the final 6 hours to indicate amountof proliferation. Wells containing no peptide are deemed the positiveresponse and there is no true background response. A percent response iscalculated as follows: (CPM experimental)/(CPM positive response). Alldata are expressed in this manner.

[0084] Mixed Lymphocyte Assay: Allogeneic murine mixed lymphocyteresponse assays were performed to determine if the gamma chain peptideswere capable of inhibiting this response as well. Assays were performedas previously described. Briefly, responder lymph node cells wereisolated from SJL mice and stimulator spleen cells were located from(B6xCBA) F₁ mice responder cells (2×10⁵/well) were plated in 96 wellplates along with irradiated stimulator cells (4×10⁵/well). Titredamounts of gamma chain peptides were added to the indicated wells.Cultures are incubated at 37° C. for 3 days and pulsed with ³H-TdR forthe final 18 hours to indicate amount of proliferation. Wells containingno peptide and both stimulator and responder cells are deemed thepositive response and wells containing no peptide and no stimulatorcells are deemed the background (bkg) proliferation. A percent responseis calculated as follows: (CPM experimental−CPM bkg)/(CPM positiveresponse−CPM bkg). All data are expressed in this manner.

[0085] In vitro testing using human cells and in vivo testing wasperformed as follows.

[0086] TF-1 Proliferation Assay: The TF-1 cell line is a human cell linethat is responsive to several cytokine including human IL-4. Inhibitionof IL-4 induced proliferation of this cell indicates that these peptidesare capable if inhibiting human IL-4. Briefly, TF-1 cells are rested(Cultured in the absence of cytokines) for 48 hours prior to theinitiation of the assay. Cells are plated (20000/well) along with titredamounts of the indicated peptides and 1 ng/ml r-hIL-4). Cultures areincubated at 37° C. for 48 hours and pulsed with ³H-TDR for the final 6hours to indicate amount of proliferation. Wells containing no peptideare deemed the positive response and wells containing no peptide and nocytokine are deemed the background (bkg) proliferation. A percentresponse is calculated as follows: (CPM experimental−CPM bkg)/(CPMpositive response−CPM bkg). All data are expressed in this manner. Theresults are shown in FIG. 7.

[0087] Effect of Gamma Chain Peptides In Vivo: In order to evaluate theefficacy of these peptides in vivo, we challenged sub-lethally (500Rads) irradiated B10.A mice with 2×10⁵ CH12 (B-cell Lymphoma) cells andtracked the lethal effects of this tumor challenge. Indicated groups ofmice (4/group) received either no treatment, gamma 2T (0.5 mg i.p. ondays 0, 3, 6), of gamma4 (0.5 mg i.p. on days 0, 3, 6). Data isrepresented as % survival. The data is shown on FIG. 8.

1 37 1 7 PRT Artificial Sequence Novel Sequence 1 Ile Gln Leu Tyr GlnThr Phe 1 5 2 7 PRT Artificial Sequence Novel Sequence 2 Ile His Leu TyrGln Thr Phe 1 5 3 5 PRT Artificial Sequence Novel Sequence 3 Cys Gln TyrLeu Val 1 5 4 6 PRT Artificial Sequence Novel Sequence 4 Cys Leu Glu HisLeu Val 1 5 5 6 PRT Artificial Sequence Novel Sequence 5 Cys Leu Gln TyrLeu Thr 1 5 6 6 PRT Artificial Sequence Novel Sequence 6 Cys Leu Glu HisLeu Thr 1 5 7 7 PRT Artificial Sequence Novel Sequence 7 Cys Leu Gln TyrLeu Thr Gln 1 5 8 7 PRT Artificial Sequence Novel Sequence 8 Cys Leu GluHis Leu Thr Gln 1 5 9 8 PRT Artificial Sequence Novel Sequence 9 Pro IleAla Gly Ser Ser Gln Gln 1 5 10 8 PRT Artificial Sequence Novel Sequence10 Pro Leu Cys Gly Ser Ala Gln His 1 5 11 8 PRT Artificial SequenceNovel Sequence 11 Pro Leu Ala Gly Ser Ala Gln His 1 5 12 8 PRTArtificial Sequence Novel Sequence 12 Asn His Glu Pro Arg Phe Leu Ser 15 13 8 PRT Artificial Sequence Novel Sequence 13 Asp Tyr Arg His Lys PheSer Leu 1 5 14 6 PRT Artificial Sequence Novel Sequence 14 Leu Asn LeuGln Asn Leu 1 5 15 6 PRT Artificial Sequence Novel Sequence 15 Leu LysLeu Gln Asn Leu 1 5 16 7 PRT Artificial Sequence Novel Sequence 16 AsnLeu Ser Glu Ser Gln Leu 1 5 17 7 PRT Artificial Sequence Novel Sequence17 Lys Leu Ser Glu Ser Gln Leu 1 5 18 9 PRT Artificial Sequence NovelSequence 18 Cys Ile Gln Leu Tyr Gln Thr Phe Cys 1 5 19 9 PRT ArtificialSequence Novel Sequence 19 Cys Ile His Leu Tyr Gln Thr Phe Cys 1 5 20 7PRT Artificial Sequence Novel Sequence 20 Cys Leu Gln Tyr Leu Val Cys 15 21 7 PRT Artificial Sequence Novel Sequence 21 Cys Leu Glu His Leu ValCys 1 5 22 7 PRT Artificial Sequence Novel Sequence 22 Cys Leu Gln TyrLeu Thr Cys 1 5 23 7 PRT Artificial Sequence Novel Sequence 23 Cys LeuGlu His Leu Thr Cys 1 5 24 8 PRT Artificial Sequence Novel Sequence 24Cys Leu Gln Tyr Leu Thr Gln Cys 1 5 25 8 PRT Artificial Sequence NovelSequence 25 Cys Leu Glu His Leu Thr Gln Cys 1 5 26 10 PRT ArtificialSequence Novel Sequence 26 Cys Pro Ile Ala Gly Ser Ser Gln Gln Cys 1 510 27 10 PRT Artificial Sequence Novel Sequence 27 Cys Pro Leu Cys GlySer Ala Gln His Cys 1 5 10 28 10 PRT Artificial Sequence Novel Sequence28 Cys Pro Leu Ala Gly Ser Ala Gln His Cys 1 5 10 29 10 PRT ArtificialSequence Novel Sequence 29 Cys Asn His Glu Pro Arg Phe Leu Ser Cys 1 510 30 10 PRT Artificial Sequence Novel Sequence 30 Cys Asp Tyr Arg HisLys Phe Ser Leu Cys 1 5 10 31 8 PRT Artificial Sequence Novel Sequence31 Cys Leu Asn Leu Gln Asn Leu Cys 1 5 32 8 PRT Artificial SequenceNovel Sequence 32 Cys Leu Lys Leu Gln Asn Leu Cys 1 5 33 9 PRTArtificial Sequence Novel Sequence 33 Cys Asn Leu Ser Glu Ser Gln LeuCys 1 5 34 9 PRT Artificial Sequence Novel Sequence 34 Cys Lys Leu SerGlu Ser Gln Leu Cys 1 5 35 10 PRT Artificial Sequence Novel Sequence 35Glu Arg Cys Leu Gln Tyr Leu Val Gln Tyr 1 5 10 36 8 PRT ArtificialSequence Novel Sequence 36 Pro Ile Cys Gly Ser Ser Gln Gln 1 5 37 10 PRTArtificial Sequence Novel Sequence 37 Cys Pro Ile Cys Gly Ser Ser GlnGln Cys 1 5 10

1. A peptide which mimics a loop on the γ-chain that either interactwith a cytokine or a γ-chain partner receptor chain of a heterodimericcytokine receptor, wherein said peptide consists of 5-25 amino acids andinhibits signal transduction mediated by cytokine:receptor binding ofcytokines that bind to receptors that comprise a γ-chain.
 2. The peptideof claim 1 wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ IDNO:2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ;SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ IDNO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17KLSEQL or such an amino acid sequence with one or more conservativesubstitutions.
 3. The peptide of claim 1 wherein said peptide includes:SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ IDNO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15LKLQNL; SEQ ID NO:16 NLSESQL or SEQ ID NO:17 KLSEQL.
 4. The peptide ofclaim 1 wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQLor such an amino acid sequence with one or more conservativesubstitutions.
 5. The peptide of claim 1 wherein said peptide isconformationally restricted.
 6. The peptide of claim 1 wherein saidpeptide is cyclic.
 7. The peptide of claim 1 wherein said peptide has acysteine residue at its N terminus and a cysteine residue at its Cterminus and it is cyclized by formation of a disulfide bond betweensaid cysteine residues.
 8. The peptide of claim 1 wherein said peptideis selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ IDNO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ IDNO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ IDNO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ IDNO:33 CNLSESQLC; SEQ ID NO:34 CKLSESQLC and derivative peptides thereof.9. The peptide of claim 1 wherein said peptide is selected from thegroup consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19 CIHLYQTFC; SEQID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22 CLQYLTC; SEQ IDNO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25 CLEHLTQC; SEQ IDNO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27 CPLCGSAQHC; SEQID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ ID NO:30 CDYRHKFSLC;SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ ID NO:33 CNLSESQLC andSEQ ID NO:34 CKLSESQLC.
 10. The peptide of claim 1 wherein said peptideis a conformationally restricted peptide having the formula:R₁—R₂—R₃—R₄—R₅ wherein: R₁ is a linking moiety; R₂ is 0-10 amino acids;R₃ is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acidsequence with one or more conservative substitutions; R₄ is 0-10 aminoacids; and R₅ is a linking moiety.
 11. The peptide of claim 10 wherein:R₁ is cysteine; and R₅ is cysteine.
 12. The peptide of claim 11 wherein:R₃ is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15LKLQNL; SEQ ID NO:16 NLSESQL; or SEQ ID NO:17 KLSEQL.
 13. The peptide ofclaim 12 wherein: R₁ is cysteine; and R₅ is cysteine.
 14. Apharmaceutical composition comprising a peptide of claim 1 and apharmaceutically acceptable carrier or diluent.
 15. The pharmaceuticalcomposition of claim 14 wherein said peptide includes: SEQ ID NO:1IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV;SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQLor such an amino acid sequence with one or more conservativesubstitutions.
 16. The pharmaceutical composition of claim 14 whereinsaid peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ IDNO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT;SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ IDNO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ IDNO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15LKLQNL; SEQ ID NO:16 NLSESQL or SEQ ID NO:17 KLSEQL.
 17. Thepharmaceutical composition of claim 14 wherein said peptide isconformationally restricted.
 18. The pharmaceutical composition of claim14 wherein said peptide is cyclic.
 19. The pharmaceutical composition ofclaim 14 wherein said peptide has a cysteine residue at its N terminusand a cysteine residue at its C terminus and it is cyclized by formationof a disulfide bond between said cysteine residues.
 20. Thepharmaceutical composition of claim 14 wherein said peptide is selectedfrom the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ IDNO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ IDNO:33 CNLSESQLC; SEQ ID NO:34 CKLSESQLC and derivative peptides thereof.21. The pharmaceutical composition of claim 14 wherein said peptide isselected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ IDNO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ IDNO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ IDNO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ IDNO:33 CNLSESQLC and SEQ ID NO:34 CKLSESQLC.
 22. The pharmaceuticalcomposition of claim 14 wherein said peptide is a conformationallyrestricted peptide having the formula: R₁—R₂—R₃—R₄—R wherein: R₁ is alinking moiety; R₂ is 0-10 amino acids; R₃ is SEQ ID NO:1 IQLYQTF; SEQID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ;SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ IDNO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17KLSEQL or such an amino acid sequence with one or more conservativesubstitutions; R₄ is 0-10 amino acids; and R₅ is a linking moiety. 23.The pharmaceutical composition of claim 14 wherein: R₁ is cysteine; andR₅ is cysteine.
 24. The pharmaceutical composition of claim 23 wherein:R₃ is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15LKLQNL; SEQ ID NO:16 NLSESQL; or SEQ ID NO:17 KLSEQL.
 25. Thepharmaceutical composition of claim 24 wherein: R₁ is cysteine; and R₅is cysteine.
 26. A method of inhibiting signal transduction mediated bycytokine:receptor binding of cytokines that bind to receptors thatcomprise a y-chain, said method comprising the step of administering aneffective amount of a peptide of claim
 1. 27. A method of inhibitingcytokine mediated cell growth, proliferation, function or activitycomprising the step of contacting said cell with an peptide of claim 1.28. A method of treating a patient suffering from a disease disorder orcondition characterized by cytokine mediated cell growth, proliferation,function or activity comprising the step of administering to saidpatient a therapeutically effective amount of a peptide of claim
 1. 29.A method of treating a patient suffering from a disease disorder orcondition characterized by cytokine mediated cell growth, proliferation,function or activity comprising the step of administering to saidpatient a therapeutically effective amount of a peptide of claim 1,wherein said patient has lymphoma, leukemia, an allergic reaction, anautoimmune disease, graft versus host disease or rejection of atransplant or graft.
 30. A method of preventing a conditioncharacterized by cytokine mediated cell growth, proliferation, functionor activity in a patient identified as being at risk of such a conditioncomprising the step of administering to said patient a prophylacticallyeffective amount of a peptide of claim
 1. 31. A method of preventing acondition characterized by cytokine mediated cell growth, proliferation,function or activity in a patient identified as being at risk of such acondition comprising the step of administering to said patient aprophylactically effective amount of a peptide of claim 1, wherein saidpatient is at risk of an allergic reaction, graft versus host disease orrejection of a transplant or graft.